The invention relates, as novel and useful industrial products, to bi-aromatic compounds whose aromatic rings are linked via a divalent heteroethynylene radical. The invention also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological complaints associated with a keratinization disorder, dermatological (or other) complaints with an inflammatory and/or immunoalergic component, and dermal or epidermal proliferations, whether they are benign or malignant. These compounds can also be used in the treatment of connective tissue degenerative diseases, for combating ageing of the skin, whether this is light-induced or chronological ageing, and for treating cicatrization disorders. They moreover find an application in the opthalmological field, in particular in the treatment of corneopathy.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
Bi-aromatic compounds whose aromatic rings are linked via a divalent propynylene have already been described in EP-661,258 as active substances in pharmaceutical or cosmetic compositions.
The compounds according to EP-661,258 correspond to the following general formula: 
in which:
Ar is a divalent aromatic radical optionally substituted with a radical R5 or a heteroaromatic radical optionally substituted with a radical R6 when the hetero atom is nitrogen,
R1 represents H, xe2x80x94CH3, xe2x80x94CH2OR6, xe2x80x94OR6, xe2x80x94COR7 or xe2x80x94S(O)tR9, t being 0, 1 or 2.
R2 and R3 represent H, C1-C20 alkyl, xe2x80x94OR6 or xe2x80x94SR6,
or R2 and R3 taken together, form a 5- or 6-membered ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulphur atom,
R4 and R5 represent H, a halogen, lower alkyl or xe2x80x94OR6,
R6 represents H, lower alkyl or xe2x80x94COR9,
R7 represents H, lower alkyl, 
or xe2x80x94OR8,
R8 represents H, linear or branched C1-C20 alkyl, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar or amino acid or peptide residue,
R9 represents lower alkyl,
R and Rxe2x80x2 represent H, lower alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl or a sugar, amino acid or peptide residue or R and Rxe2x80x2, taken together, form a heterocycle, and
X represents a divalent radical which, from right to left or vice-versa, has the formula: 
in which:
R10 represents H, lower alkyl or xe2x80x94OR6,
R11 represents xe2x80x94OR6,
or R10 and R11, taken together, form an oxo (xe2x95x90O) radical,
and the salts of the said compounds of the above formula when R1 represents a carboxylic acid function, and the optical and geometrical isomers of these said compounds.
The compounds according to the present invention differ from those of EP-661,258 essentially in that the radical X or divalent propynylene radical has been replaced with a divalent heteroethynylene radical.
The reason for this is that it has been found, surprisingly and unexpectedly, that this structural change makes it possible to significantly increase the pharmaceutical and cosmetic properties thereof and also to decrease certain side effects thereof.
A subject of the present invention is thus novel compounds which can be represented by the following general formula: 
in which:
Ar represents a radical chosen from the formulae (a) to (c) below: 
Z being O or S, or Nxe2x80x94R6,
R1 represents a halogen atom, xe2x80x94CH3, xe2x80x94CH2xe2x80x94OR7, xe2x80x94OR7, xe2x80x94COR8 or a polyether radical,
R2 and R3, which may be identical or different, represent H, linear or branched C1-C20 alkyl, C3-C12 cycloalkyl, xe2x80x94OR7 or xe2x80x94SR7, at least one from among R2 and R3 being linear or branched C1-C20 alkyl or C3-C10 cycloalkyl, or
R2 and R3, taken together, form a 5- or 6-membered ring, optionally substituted with at least one methyl and/or optionally interrupted by a hetero atom chosen from O and S, p R4 and R5 represent H, a halogen atom, linear or branched C1-C20 alkyl, xe2x80x94OR7 or a polyether radical,
R6 represents H, linear or branched C1-C10 alkyl or xe2x80x94OCOR9,
R7 represents H, linear or branched C1-C10 alkyl or xe2x80x94COR9,
R8 represents H, linear or branched C1-C10, alkyl, xe2x80x94OR10 or 
R9 represents linear or branched C1-C10 alkyl,
R10 represents H, linear or branched C1-C20 alkyl, mono- or polyhydroxvalkyl, allyl, optionally substituted aryl or aralkyl, or a sugar residue,
rxe2x80x2 and rxe2x80x3, which may be identical or different, represent H, C1-C10 alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, an amino acid or peptide residue, or, taken together with the nitrogen atom, form a heterocycle,
X represents a divalent radical which, from right to left or vice-versa, has the formula: 
in which:
Y represents O, S(O)n or Se(O)nxe2x80x2,
n and nxe2x80x2 being 0, 1 or 2,
with the proviso that when n=2 and Ar is a radical of formula (a) above, in which R1=xe2x80x94CH3 and R5=H, then at least one of the radicals R2 or R3 is other than xe2x80x94CH3,
and the salts of the compounds of formula (I) when R1 represents a carboxylic acid function, as well as the optical isomers of the said compounds of formula (I).
When the compounds according to the invention are in the form of a salt, this is preferably a salt of an alkali metal or alkaline-earth metal, or alternatively of zinc or of an organic amine.
According to the present invention, the term xe2x80x9cC1-C10 alkylxe2x80x9d preferably refers to the methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, 2-ethylhexyl and octyl radicals.
The term xe2x80x9clinear or branched C1-C20 alkylxe2x80x9d refers in particular to the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
The term xe2x80x9cC3-C12 cycloalkyl radicalxe2x80x9d refers to a mono- or polycyclic radical, in particular the cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclo-hexyl and 1-adamantyl radicals.
The term xe2x80x9cpolyether radicalxe2x80x9d refers to a radical containing from 2 to 5 carbon atoms interrupted by at least two oxygen atoms, such as the methyloxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
The term xe2x80x9cmonohydroxyalkylxe2x80x9d refers to a radical preferably containing 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
The term xe2x80x9cpolyhydroxyalkylxe2x80x9d refers to a radical preferably containing 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.
The term xe2x80x9carylxe2x80x9d preferably refers to a phenyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
The term xe2x80x9caralkyloxe2x80x9d preferably refers to a benzyl or phenethyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
The term xe2x80x9csugar residuexe2x80x9d refers to a residue derived in particular from glucose, from galactose or from mannose, or alternatively from glucuronic acid.
The term xe2x80x9camino acid residuesxe2x80x9d refers in particular to a residue derived from lysine, from glycine or from aspartic acid, and the term xe2x80x9cpeptide residuexe2x80x9d refers more particularly to a dipeptide or tripeptide residue resulting from the combination of amino acids.
The term xe2x80x9cheterocyclexe2x80x9d preferably refers to a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in position 4 with a C1-C6 lower alkyl or a mono- or polyhydroxyalkyl as defined above.
When R1, R4 and/or R5 represents a halogen atom, this is preferably a fluorine, chlorine or bromine atom.
According to a first preferred embodiment, the compounds according to the invention correspond to the following general formula: 
in which:
Arxe2x80x2 represents a radical of formula: 
R1, R4, R5 and X being as defined above for formula (I),
R11, R12, R13 and R14, which may be identical or different, represent H or xe2x80x94CH3, and
n is 1 or 2.
According to a second preferred embodiment, the compounds according to the invention correspond to the following formula: 
in which:
W represents O or S,
R4, R11, R12, Arxe2x80x2 and X being as defined above in the formulae (I) and (II).
Lastly, according to a third preferred embodiment, the compounds according to the invention correspond to the following formula: 
in which:
R4, Arxe2x80x2 and X are as defined above in formulae (I) to (III), and
at least one of the radicals Rxe2x80x22 and/or Rxe2x80x23 represents a mono- or polycyclic C5-C10 cycloalkyl radical, the other representing one of the meanings given for R2 or R3.
Among the compounds of formulae (I) to (IV) above, according to the present invention, mention may be made in particular of the following:
Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylehynyl)benzoic acid,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl)benzoic acid,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoic acid,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphonylethynyl)benzoic acid,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphinylethynyl)benzoic acid,
Methyl 4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
4-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
Methyl 2-hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
2-Hydroxy-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
6-(4-methoxymethoxyphenylethynylselanyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,
Ethyl 6-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,
6-(5,5,8,8,-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid,
N-(4-Hydroxyphenyl)-4-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzamide,
Methyl 5-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridime carboxylate,
2-(4-Chlorophenylselanylethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,
Methyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzaic acid,
Methyl 2-hydroxy-4-(3,5,5,8,8-pentamethlyl-5,6,7,8-tetahydro-2-naphthylselanylethynyl)benzoate,
2-Hydroxy-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
Ethyl 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate,
6-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid,
N-(4-Hydroxyphenyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,
N-Butyl-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinamide,
Morpholin-4-yl-[6-(3,5,5,8,8,-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-3-pyridyl]methanone,
Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napathylselanylethynyl)pyridine-2-carboxylate,
5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2naphthylselanylethynyl)pyridine-2-carboxylic acid,
[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]methanol,
Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate,
Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoate,
Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoate,
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoic acid,
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphonyl)benzoic acid,
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphinyl)benzoic acid,
4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenol,
Ethyl 4-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
Ethyl 4-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
4-(4-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
4-(4-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
Ethyl 4-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
Ethyl 4-(3-methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
4-(3-Methoxyethoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
4-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
Ethyl 4-(3-pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoate,
4-(3-Pentyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid,
[4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)phenyl]carbaldehyde,
Methyl 4-(4,4-dimethylthiochroman-8-ylselanylethynyl)benzoate,
4-(4,4-Dimethylthiochroman-8-ylselanylethynyl)benzoic acid,
Methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoate,
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-8-naphthylselanylethynyl)benzoic acid,
Methyl 4-[3-(1-adamantyl)-4-methoxyphenyl)-1-ylselanylethynyl]benzoate,
4-[3-(1-Adamantyl)-4-methoxyphenyl))-1-ylselanylethynyl]benzoic acid,
Methyl 4-[4-(1-adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoate, and
4-[4-(1-Adamantyl)-3-methoxyphenyl)-1-ylselanylethynyl]benzoic acid.
A subject of the present invention is also the processes for preparing the compounds of formula (I) above according to the reaction schemes given in Tables A and B.
With reference to Table A, the compounds of formula (I) in which X represents the divalent radical 
i.e. the compounds of formula (Ia), can be obtained according to two different synthetic routes depending on whether Y=oxygen or Yxe2x89xa0oxygen.
When X=oxygen, the starting material is the compound of formula (1), which, in the presence of a base such as potassium hydride or sodium hydride, is then coupled with trichloroethylene. The dichloroethylene product obtained, of formula (2), is then subjected to the action of a lithiated base, such as butyllithium, in a solvent such as THF, to give the acetylenic compound of formula (3). This acetylene is then coupled with an aryl halide or a heteroaryl halide, preferably an iodo derivative, in the presence of a palladium catalyst to give the compounds of formula (IIa) with Y=oxygen.
When Yxe2x89xa0oxygen, the lithium acetylide of formula (5) is first prepared, from the aromatic or heteroaromatic acetylenic compound (4), in the presence of a lithiated derivative such as butyllithium, in a solvent such as THF. Starting with the lithium acetylide (5), which is not isolated, a coupling is carried out with the compound of formula (6), in a solvent such as THF, to give the compounds of formula (Ia) with Yxe2x89xa0oxygen.
Starting with these compounds of formula (Ia) in which Y=S or Se, it is possible to gain access to the oxidized derivatives by oxidation using an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodium periodate.
With reference now to Table B, the compounds of formula (I), in which X represents a divalent radical 
i.e. the compounds of formula (Ic), can also be obtained according to two different synthetic routes depending an whether Y=oxygen or Yxe2x89xa0oxygen.
When Y=oxygen, the starting material is an aromatic or heteroaromatic compound of formula (7), which, in the presence of a base such as potassium hydride or sodium hydride, in a solvent such as THF, is then coupled with trichloroethylene. The dichloro-ethylene product obtained (8) is then subjected to the action of a lithiated base such as butyllithium, in THF, to give the oxoacetylenic compound of formula (9). This acetylene is then coupled with an aryl halide (10), preferably an iodo derivative, in the presence of a palladium catalyst, to give the compounds of formula (Ic) with Y=oxygen.
When Yxe2x89xa0oxygen; the starting material is an aromatic acetylenic compound of formula (11), which is converted into a lithiated derivative in the presence of butyllithium, for example in a solvent such as THF. The lithiated acetylenic derivative (12), which is not isolated, is then coupled with an aromatic or heteroaromatic compound of formula (13), the coupling reaction being carried out in a solvent such as THF. The compounds of formula (Ic) with Yxe2x89xa0oxygen are thus obtained by this synthetic route.
Starting with these compounds of formula (Ic), in which Y=S or Se, it is also possible to obtain the oxidized derivatives by oxidation using an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodium periodate.
When, in the compounds according to the invention, the radical R1 represents xe2x80x94COOH, these radicals are prepared by protecting the carboxylic acid function with a protecting group or the alkyl type.
By saponification of ester function in the presence of a base such as sodium hydroxide or lithium hydroxide in an alcoholic solvent or in THF, the corresponding free acids are thus obtained.
When R1 is xe2x80x94OH, the compounds can be obtained from the corresponding acid by reduction in the presence of hydride such as boron hydride.
When R1 is xe2x80x94CHxe2x95x90O, the compounds can be obtained by oxidation of the corresponding alcohols using manganese oxide or pyridinium dichromate.
When R1 is 
the compounds can be obtained by conversion of the corresponding acid into the acid chloride, for example with thionyl chloride, followed by reaction with aqueous ammonia or a suitable amine.
A subject of the present invention is also the compounds of formula (I) as defined above, as medicinal products.
The compounds of general formula (I) have agonist or antagonist activity with respect to the expression of one or more biological markers in the test of differentiation of mouse embryonic teratocarcinoma cells (F9) (Skin Pharmacol. 3, p. 256-267, 1990) and/or on the in vitro differentiation of human keratinocytes (Skin Pharmacol. 3, p. 70-85, 1990). These abovementioned tests show the activities of the compounds in the fields of differentiation and proliferation. The activities can also be measured in cellular transactivation tests using RAR recombinant receptors according to the method by B. A. Bernard et al., Biochemical and Biophysical Research Communication, vol. 186, 977-983, 1992.
The compounds according to the invention are particularly suitable in the following fields of treatment:
1) for treating dermatological complaints associated with a keratinization disorder which has a bearing on differentiation and on proliferation, in particular for treating common acne, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medication-related or occupational acne,
2 ) for treating other types of keratinization disorder, in particular ichthyosis, ichthyosiform states, Darier""s disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, and cutaneous or mucous (buccal) lichen,
3) for treating other dermatological complaints associated with a keratinization disorder with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether it is cutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory complaints which have no keratinization disorder;
4) for treating all dermal or epidermal proliferations, whether benign or malignant and whether they are of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, it being also possible for the oral or florid papillomatoses and the proliferations to be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma,
5) for treating other dermatological disorders such as bullosis and collagen diseases,
6) for treating certain ophthalmological disorders, in particular corneopathies,
7) for repairing or combating ageing of the skin, whether this is light-induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic ageing,
8) for preventing or curing the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) for preventing or treating cicatrization disorders or for preventing or repairing stretch marks,
10) for combating disorders of sebaceous functioning such as the hyperseborrhoea of acne or simple seborrhoea,
11) in the treatment or prevention of cancerous or precancerous states,
12) in the treatment of inflammatory complaints such as arthritis,
13) in the treatment of any general or skin complaint of viral origin,
14) in the prevention or treatment or alopecia,
15) in the treatment of dermatological or general complaints having an immunological component, and 16) in the treatment of complaints of the cardiovascular system such as arteriosclerosis.
In the therapeutic fields mentioned above, the compounds according to the invention mar be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers. The expression xe2x80x9cD vitamins or derivatives thereofxe2x80x9d means, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3. The expression xe2x80x9canti-free-radical agentsxe2x80x9d means, for example, xcex1-tocopherol, superoxide dismutase or SOD, ubiquinol or certain metal-chelating agents. The expression xe2x80x9cxcex1-hydroxy or xcex1-keto acids or derivatives thereofxe2x80x9d means, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acid or the salts, amides or esters thereof. Lastly, the term xe2x80x9cion-channel blockersxe2x80x9d means, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereon.
A subject of the present invention is also pharmaceutical compositions containing at least one compound of formula (I) as defined above, one of the optical or geometrical isomers thereof or one of the salts thereof.
The pharmaceutical compositions are intended in particular for treating the abovementioned complaints, and are characterized in that they comprise a pharmaceutically acceptable support which is compatible with the mode of administration selected, at least one compound of formula (I), one of the optical or geometrical isomers thereof or one of the salts thereof.
The compounds according to the invention may be administered enterally, parenterally, topically or ocularly.
Via the enteral route, the compositions may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or polymeric or lipid vesicles which enable controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight taken in 1 to 3 doses.
Via the topical route, the pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and the mucosae and may then be in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or polymeric or lipid vesicles or polymeric patches and hydrogels which enable controlled release of the active principle. Furthermore, these topical-route compositions may either be in anhydrous form or in aqueous form, depending on the clinical indication.
Via the ocular route, they are mainly eyedrops.
These compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of the optical or geometrical isomers thereof or alternatively one of the salts thereof, at a concentration preferably of between 0.001% and 5% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene and especially for treating skin types with a tendency towards acne, for promoting the regrowth of the hair, for combating hair loss, for combating the greasy appearance of the skin or the hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin types, and for preventing and/or combating light-induced or chronological ageing.
In the cosmetic field, the compounds according to the invention can moreover be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers, all or these latter compounds being as defined above.
The present invention is thus also directed towards a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable support, at least one compound of formula (I) as defined above or one of the optical or geometrical isomers thereof or one of the salts thereof, it being possible for the said cosmetic composition to be, in particular, in the form or a cream, a milk, a lotion, a gel, microspheres or nanospheres or polymeric or lipid vesicles, a soap or a shampoo.
The concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight relative to the total weight of the composition.
The pharmaceutical and cosmetic compositions according to the invention can also contain inert additives or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG-400, thiomorpholino and derivatives thereof, or urea; anti-seborrhoea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, the salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidinocyrimidine-3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4-diphenyl-imidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular, xcex2-carotene; anti-psoriatic agents such as anthraline and derivatives thereof and, lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, the esters and amides thereof.
The compositions according to the invention may also contain flavour-enhancing agents, preserving agents such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as xcex1-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
Several examples for obtaining the active compounds of formula (I) according to the invention, as well as various cosmetic and pharmaceutical formulations based on such compounds, will now be given for illustrative purposes and with no limiting nature.